The goal of this Project is to examine the mechanisms by which xenogeneic islets are rejected and to determine whether islet manipulations performed in other Projects of this Program lead to better survival of islet transplants. Published studies have not yet determined whether humoral responses play a role in the destruction of xenogeneic islets. In addition, studies of cellular rejection mechanisms have not yet clarified whether direct or indirect T cell responses and whether Th1 or Th2 cytokine production are primarily responsible for islet rejection. Preliminary data from the P.I.'s laboratory, using several genetically engineered mouse strains and therapies have emphasized the importance of CD4+ cells stimulated indirectly in xenograft rejection. However, they have also suggested that unusual signaling mechanisms and have preformed roughly 20 xenogeneic islet transplants to monkeys. With this background the experiments in this project will test the hypothesis that xenogeneic islet rejection is mediated primarily by CD4+ indirect responses which generate inflammatory cytokines, causing islet destruction through the function of variety of non-specific cell-types and molecules. In the first specific aim, we will determine whether humoral immunity can cause islet destruction using the passive transfer of antibodies into Scid recipients of pig islet transplants. In the second specific aim, we will examine the cellular mechanisms of pig islet rejection using several genetically altered mouse strains which utilize direct versus indirect pathways or which produce Th1 versus Th2 cytokine responses. In the third specific aim, we will perform pig islet transplants into monkeys, using therapeutic manipulations based on the findings of the initial two aims. The experiments in this Project will be performed in cooperation with the other Project Leaders of this Program. Islets which have been manipulated by other investigators will be used for the transplantation experiments in this Project, both to determine whether they produce prolonged survival and to learn more about the mechanisms of rejection. In turn, as we learn more about the mechanisms of islet rejection, we will suggest additional therapeutic manipulations which can be undertaken by t he other project leaders. Together, these studies will allow us to progress toward the successful transplantation of pig islets into primate recipients, in preparation for the eventual clinical application of xenogeneic islet transplantation to treat Diabetes.